EMERGING SARS-COV-2 VARIANTS: CONSIDERATIONS FOR VACCINE - ACIP COVID-19 VACCINES - CDC PRESENTATION
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ACIP COVID-19 Vaccines
Emerging SARS-CoV-2 Variants:
Considerations for Vaccine
CDR Heather Scobie PhD, MPH
ACIP Meeting
March 1, 2021
For more information: www.cdc.gov/COVID19
Background
SARS-CoV-2 Variants
▪ Multiple SARS-CoV-2 variants circulating globally
– After emerging, some disappear; others persist
▪ CDC and others are studying these variants to understand whether they:
– Spread more easily from person to person
– Cause milder or more severe disease in people
– Detected by available diagnostic tests
– Respond to therapeutics currently used to treat people for COVID-19
– Change effectiveness of COVID-19 vaccines
▪ Variants classified, e.g., "variant of concern"
https://www.cdc.gov/coronavirus/2019-ncov/transmission/variant.html
https://www.who.int/publications/m/item/covid-19-weekly-epidemiological-update
Why are new SARS-CoV-2 variants emerging?
▪ Viruses constantly change through mutation, so new variants are expected
– SARS-CoV-2 has low mutation rate, compared with influenza and HIV
▪ Evolutionary selection — still being characterized, may be driven by:
– Chronic infection (e.g., immunocompromised)
– Interspecies transmission (e.g., minks)
– Therapeutic treatment (e.g., monoclonal antibodies, convalescent sera)
– Prior immunity to strains with limited cross-reactivity
– Increased transmissibility
– Founder effect — small number of genotypes seed a new population
Example of SARS-CoV-2 strain replacement
D614G – worldwide
▪ Greater infectivity, more open
conformation of viral spike
protein
▪ Likely increased transmissibility
(20%)
▪ Not more clinically severe
▪ Current vaccines are still
highly effective
Figure source: Callaway E. Nature (2020). https://www.nature.com/articles/d41586-020-02544-6
Volz et al. Cell (2021). https://www.sciencedirect.com/science/article/pii/S0092867420315373
https://www.cdc.gov/coronavirus/2019-ncov/more/science-and-research/scientific-brief-emerging-variants.html#ref2
Example of SARS-CoV-2 strain replacement Spike
proteins
D614G – worldwide
▪ Greater infectivity, more open
conformation of viral spike
protein
▪ Likely increased transmissibility
(20%)
▪ Not more clinically severe
▪ Current vaccines are still
highly effective
Figure source: Callaway E. Nature (2020). https://www.nature.com/articles/d41586-020-02544-6
Volz et al. Cell (2021). https://www.sciencedirect.com/science/article/pii/S0092867420315373
https://www.cdc.gov/coronavirus/2019-ncov/more/science-and-research/scientific-brief-emerging-variants.html#ref2SARS-CoV-2 variants of concern
Countries
Name Name First Cases in Reporting Key Amino Acid Transmissibility
(Pangolin) (Nextstrain) Detected the US Cases Mutations Rate
Δ69/70
Δ144Y
United N501Y
B.1.1.7 20I/501Y.V1 Y 101 ~50% increase
Kingdom A570D
D614G
P681H
K417N
E484K
B.1.351 20H/501Y.V2 South Africa Y 51 ~50% increase
N501Y
D614G
E484K
Brazil/ K417N/T
P.1 20J/501Y.V3 Y 29 Not determined
Japan N501Y
D614G
https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/variant-surveillance/variant-info.html
Davies et al. Estimated transmissibility and severity of novel SARS-CoV-2 Variant of Concern 202012/01 in England. medrxiv.org/content/10.1101/2020.12.24.20248822v2
Pearson et al. Estimates of severity and transmissibility of novel SARS-CoV-2 variant 501Y.V2 in South Africa. https://cmmid.github.io/topics/covid19/reports/sa-novel-
variant/2021_01_11_Transmissibility_and_severity_of_501Y_V2_in_SA.pdfSARS-CoV-2 variants of concern
Countries
Name Name First Cases in Reporting Key Amino Acid Transmissibility
(Pangolin) (Nextstrain) Detected the US Cases Mutations Rate
Δ69/70
Δ144Y
United N501Y
B.1.1.7 20I/501Y.V1 Y 101 ~50% increase
Kingdom A570D
D614G
P681H
K417N
E484K
B.1.351 20H/501Y.V2 South Africa Y 51 ~50% increase
N501Y
D614G
E484K
Brazil/ K417N/T
P.1 20J/501Y.V3 Y 29 Not determined
Japan N501Y
D614G
https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/variant-surveillance/variant-info.html
Davies et al. Estimated transmissibility and severity of novel SARS-CoV-2 Variant of Concern 202012/01 in England. medrxiv.org/content/10.1101/2020.12.24.20248822v2
Pearson et al. Estimates of severity and transmissibility of novel SARS-CoV-2 variant 501Y.V2 in South Africa. https://cmmid.github.io/topics/covid19/reports/sa-novel-
variant/2021_01_11_Transmissibility_and_severity_of_501Y_V2_in_SA.pdfSARS-CoV-2 variants of concern
Countries
Name Name First Cases in Reporting Key Amino Acid Transmissibility
(Pangolin) (Nextstrain) Detected the US Cases Mutations Rate
Δ69/70
Δ144Y
United N501Y
B.1.1.7 20I/501Y.V1 Y 101 ~50% increase
Kingdom A570D
D614G
P681H
K417N
E484K
B.1.351 20H/501Y.V2 South Africa Y 51 ~50% increase
N501Y
D614G
E484K
Brazil/ K417N/T
P.1 20J/501Y.V3 Y 29 Not determined
Japan N501Y
D614G
https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/variant-surveillance/variant-info.html
Davies et al. Estimated transmissibility and severity of novel SARS-CoV-2 Variant of Concern 202012/01 in England. medrxiv.org/content/10.1101/2020.12.24.20248822v2
Pearson et al. Estimates of severity and transmissibility of novel SARS-CoV-2 variant 501Y.V2 in South Africa. https://cmmid.github.io/topics/covid19/reports/sa-novel-
variant/2021_01_11_Transmissibility_and_severity_of_501Y_V2_in_SA.pdfSARS-CoV-2 variants of concern
Countries
Name Name First Cases in Reporting Key Amino Acid Transmissibility
(Pangolin) (Nextstrain) Detected the US Cases Mutations Rate
Δ69/70
Δ144Y
United
Glutamic Acid (E) N501Y
B.1.1.7 20I/501Y.V1 Y to Lysine101
(K) ~50% increase
Kingdom
replacement at spike position 484: A570D
D614G
− to + charge change
P681H
K417N
E484K
B.1.351 20H/501Y.V2 South Africa Y 51 ~50% increase
N501Y
D614G
E484K
Brazil/ K417N/T
P.1 20J/501Y.V3 Y 29 Not determined
Japan N501Y
D614G
https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/variant-surveillance/variant-info.html
Davies et al. Estimated transmissibility and severity of novel SARS-CoV-2 Variant of Concern 202012/01 in England. medrxiv.org/content/10.1101/2020.12.24.20248822v2
Pearson et al. Estimates of severity and transmissibility of novel SARS-CoV-2 variant 501Y.V2 in South Africa. https://cmmid.github.io/topics/covid19/reports/sa-novel-
variant/2021_01_11_Transmissibility_and_severity_of_501Y_V2_in_SA.pdfU.S. COVID-19 cases caused by
variants of concern B.1.1.7
Variant Reported No. of states
cases
B.1.1.7 2,400 46
B.1.351
B.1.351 53 16
P.1 10 5
Reporting sources vary, so calculating
proportions is not possible P.1
https://www.cdc.gov/coronavirus/2019-ncov/transmission/variant-cases.html; data as of 02/28/2021B.1.1.7 trajectory in the United States
▪ First identified in Dec. 2020, but likely
arrived in Nov. 2020
– Multiple introductions
▪ Current prevalence estimated 1-2%
– Commercial diagnostic data suggest
early phase logistic expansion
▪ Two models suggest B.1.1.7 may
predominate by March 2021
– One suggests high vaccine coverage will
blunt impact of higher transmissibility
https://www.cdc.gov/coronavirus/2019-ncov/more/science-and-research/scientific-brief-emerging-variants.html
Figure source: Washington et al. medRxiv preprint (Feb 7 2021): https://www.medrxiv.org/content/10.1101/2021.02.06.21251159v1
Galloway et al. MMWR 2021;70:95–99. https://www.cdc.gov/mmwr/volumes/70/wr/mm7003e2.htm?s_cid=mm7003e2_wChanges in receptor-binding domain (RBD) of spike protein
▪ RBD binds host ACE2 receptor – essential for infection
▪ Majority of neutralizing antibodies bind RBD in most
convalescent human sera
▪ Convergent evolution of several RBD mutations
– ↑ binding, ↑ infectivity, ↓ efficacy of antibody therapies
https://www.nytimes.com/interactive/2021/health/
coronavirus-variant-tracker.htmlChanges in receptor-binding domain (RBD) of spike protein
▪ RBD binds host ACE2 receptor – essential for infection
▪ Majority of neutralizing antibodies bind RBD in most
convalescent human sera
▪ Convergent evolution of several RBD mutations
– ↑ binding, ↑ infectivity, ↓ efficacy of antibody therapies
P.2
https://www.nytimes.com/interactive/2021/health/
coronavirus-variant-tracker.htmlVaccine effectiveness data
Review of 26 studies: Vaccine sera neutralization of
SARS-CoV-2 variants
▪ 8 published studies and 18 preprint studies; all small sample sizes (n=5−50)
▪ 13 studies only Pfizer; 3 studies only Moderna; 2 studies on AstraZeneca; 7
studies on ≥1 vaccine; 1 study on unspecified mRNA vaccine
▪ 8 studies on single/limited sets of mutations – generally minimal impact
– E484K and E484K-K417N-N501Y larger effects*
▪ Largest impacts: B.1.351 (South Africa) > P.1, P.2 (Brazil) > B.1.1.7 (UK)
– Most B.1.351 studies: 3−11-fold reduction, ranged up to 97-fold
– Most B.1.1.7 studies:Reduced neutralization activity of vaccine sera relative
to wildtype/dominant strain, by study (n=22)
100
Fold reduction
Studies by vaccine type
mRNA (Pfizer or Moderna)
10
Novavax
AstraZeneca
No effect = 1
B.1.1.7 B.1.351 P.1 P.2 E484K B.1.1.7
UK S. Africa Brazil Brazil + E484K
References in AppendixNeutralization of variants after 1 & 2 vaccine doses
▪ Postponing 2nd mRNA dose may leave 1 dose
some less protected against variants Week 2 Week 3
▪ Minimal/no neutralization of B.1.351
after one dose
– History of COVID-19 + 1 dose →
moderate protection against B.1.351
▪ Improved neutralization of B.1.1.7 and
B.1.351 after 2nd dose
▪ Delayed antibody response against Pfizer vaccine
variants Figure Source: Planas et al. bioRxiv preprint (Feb 12 2021: https://doi.org/10.1101/2021.02.12.430472
Skelly et al. Res square preprint (Feb 9 2021); https://www.researchsquare.com/article/rs-226857/v1
Garcia-Beltran et al. medRxiv preprint (Feb 14 2021): https://doi.org/10.1101/2021.02.14.21251704
Shen et al. bioRxiv preprint (Jan 28 2021); https://doi.org/10.1101/2021.01.27.428516
Collier et al. medRxiv preprint (Feb 15 2021): https://doi.org/10.1101/2021.01.19.21249840
Stamatatos et al. medRxiv preprint (Feb 5 2021): https://doi.org/10.1101/2021.02.05.21251182
Supasa et al.Cell (2021): https://doi.org/10.1016/j.cell.2021.02.033Neutralization of variants after 1 & 2 vaccine doses
▪ Postponing 2nd mRNA dose may leave 1 dose 2 doses
some less protected against variants Week 2 Week 3 Week 4
▪ Minimal/no neutralization of B.1.351
after one dose
– History of COVID-19 + 1 dose →
moderate protection against B.1.351
▪ Improved neutralization of B.1.1.7 and
B.1.351 after 2nd dose
▪ Delayed antibody response against Pfizer vaccine
variants Figure Source: Planas et al. bioRxiv preprint (Feb 12 2021: https://doi.org/10.1101/2021.02.12.430472
Skelly et al. Res square preprint (Feb 9 2021); https://www.researchsquare.com/article/rs-226857/v1
Garcia-Beltran et al. medRxiv preprint (Feb 14 2021): https://doi.org/10.1101/2021.02.14.21251704
Shen et al. bioRxiv preprint (Jan 28 2021); https://doi.org/10.1101/2021.01.27.428516
Collier et al. medRxiv preprint (Feb 15 2021): https://doi.org/10.1101/2021.01.19.21249840
Stamatatos et al. medRxiv preprint (Feb 5 2021): https://doi.org/10.1101/2021.02.05.21251182
Supasa et al.Cell (2021): https://doi.org/10.1016/j.cell.2021.02.033Discussion of lab studies
▪ Difficult to estimate how laboratory results might translate to clinical protection
– No immunological correlate of protection for SARS-CoV-2
▪ Neutralization antibodies in sera from mRNA vaccine recipients generally shown to be
higher than COVID-19 convalescent sera
▪ Variation in results may be explained by differences in experimental conditions
– Neutralization assays — replicating & nonreplicating pseudovirus vs. SARS-CoV-2
– Sera — time post-vaccination, or population (e.g., age, COVID-19 history)
– Use of limited or full sets of spike mutations vs. clinical isolates of variants
▪ AstraZeneca — not prefusion stabilized spike, limited generalizability to other vaccines
▪ Limitation for all studies — small sample sizes and lack generalizability
– Many studies are preprints not yet peer-reviewedVaccine efficacy or effectiveness (VE) against variants
Vaccine Study type VE
Pfizer Post-licensure • 86% in UK (predominate B.1.1.7 circulation)*
• 94% in Israel (up to 80% of cases from B.1.1.7)
Janssen Pre-licensure • 74% in U.S.
• 66% in Brazil (69% of cases from P.2)
• 52% in S. Africa (95% of cases from B.1.351)
Novavax Pre-licensure • 96% against non-B.1.1.7 in UK
• 86% against B.1.1.7 in UK
Pre-licensure • 60% in S. Africa (93% of cases from B.1.351)
AstraZeneca Pre-licensure • 84% against non-B.1.1.7 in UK
• 75% against B.1.1.7 in UK
Pre-licensure • 10% against B.1.351 in South Africa
Hall et al. Lancet preprint (Feb 22 2021): https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3790399; *VE for symptomatic & asymptomatic infection
Dagan et al. NEJM (2021). https://www.nejm.org/doi/full/10.1056/NEJMoa2101765?query=TOC
https://www.fda.gov/media/146217/download
Novavax.: https://ir.novavax.com/news-releases/news-release-details/novavax-covid-19-vaccine-demonstrates-893-efficacy-uk-phase-3
Madhi et al. medRxiv preprint (Feb 12 2021): https://doi.org/10.1101/2021.02.10.21251247
Emary et al. Lancet preprint (Feb 4 2021): https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3779160Vaccine efficacy or effectiveness (VE) against variants
Vaccine Study type VE
Pfizer Post-licensure • 86% in UK (predominate B.1.1.7 circulation)*
• 94% in Israel (up to 80% of cases from B.1.1.7)
Janssen Pre-licensure • 74% in U.S.
73-82% for severe/critical
• 66% in Brazil
disease in each country
• 52% in S. Africa
Novavax Pre-licensure • 96% against non-B.1.1.7 in UK
• 86% against B.1.1.7 in UK
Pre-licensure • 60% in S. Africa (93% of cases from B.1.351)
AstraZeneca Pre-licensure • 84% against non-B.1.1.7 in UK
• 75% against B.1.1.7 in UK
Pre-licensure • 10% against B.1.351 in South Africa
Hall et al. Lancet preprint (Feb 22 2021): https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3790399; *VE for symptomatic & asymptomatic infection
Dagan et al. NEJM (2021). https://www.nejm.org/doi/full/10.1056/NEJMoa2101765?query=TOC
https://www.fda.gov/media/146217/download
Novavax.: https://ir.novavax.com/news-releases/news-release-details/novavax-covid-19-vaccine-demonstrates-893-efficacy-uk-phase-3
Madhi et al. medRxiv preprint (Feb 12 2021): https://doi.org/10.1101/2021.02.10.21251247
Emary et al. Lancet preprint (Feb 4 2021): https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3779160Summary of preliminary data: Implications of SARS-
CoV-2 variants of concern on vaccine effectiveness
▪ B.1.1.7 (first detected in the United Kingdom)
– Exponential increase in prevalence in United States
– Minimal impact on vaccine effectiveness, but attention needed for variants
with additional substitutions in RBD, such as E484K
▪ B.1.351 (first detected in South Africa)
– Currently low prevalence in United States
– Moderate impact on vaccine effectiveness, suggests it’s prudent to start
evaluating variant vaccines in case prevalence substantially increases
▪ P.1 (first detected in Brazil/Japan)
– Very low prevalence in United States, but same three RBD mutations as B.1.351
– Additional data needed on potential impact on vaccine effectivenessModifying vaccines to target SARS-CoV-2 variants
▪ Current prevention measures and licensed vaccines offer protection against
SARS-CoV-2 variants
– Efforts needed to increase speed and degree of uptake
▪ Periodic update of SARS-CoV-2 vaccines likely needed
▪ Modeling study predicts changing COVID-19 vaccines to target faster
spreading viral variants more effective than targeting the slower dominant
strain, despite initial prevalence 1
1. Bedwick et al. medRxiv preprint (Feb 8 2021); doi: https://doi.org/10.1101/2021.01.05.21249255Response to variants
SARS-CoV-2 Interagency Group (SIG)
▪ Established by Dept. of Health & Human Services to improve coordination
– CDC
– National Institutes of Health (NIH)
– Food and Drug Administration (FDA)
– Biomedical Advanced Research and Development Authority (BARDA)
– US Department of Agriculture (USDA)
– Department of Defense (DoD)
▪ Focuses on rapid characterization of emerging variants and monitors
potential impact on SARS-CoV-2 diagnostics, therapeutics, and vaccines
Walensky, Walke and Fauci. JAMA (2021): https://jamanetwork.com/journals/jama/fullarticle/2776739CDC approaches to genomic surveillance and
epidemiology
▪ National SARS-CoV-2 Strain Surveillance (NS3)
– Approximately 3,000 random specimens/month regularly submitted from public
health laboratories across U.S.
▪ Partnership with commercial diagnostic laboratories
– Scaling to 6,000 sequences/week
▪ Contracts and partnerships with state and local health departments and universities
▪ SPHERES* Consortium of ~170 domestic partners — open sharing of sequencing data
▪ Focused molecular epidemiologic studies
* SPHERES= SARS-CoV-2 Sequencing for Public Health Emergency Response, Epidemiology, and Surveillance
https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/variant-surveillance.html
https://www.aphl.org/programs/preparedness/Crisis-Management/COVID-19-Response/Pages/Sequence-Based-Surveillance-Submission.aspx
https://www.cdc.gov/coronavirus/2019-ncov/covid-data/spheres.htmlU.S. sequences available in public repositories
160,000
140,000 Data
collection
120,000
ongoing
100,000
80,000
60,000
40,000
20,000
0
https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/variant-surveillance/genomic-surveillance-dashboard.html as of 2/28/21
National Center for Biotechnology Information (NCBI); GISAID, a global initiative maintaining a repository of viral sequencing dataInvestigating COVID-19 vaccine breakthrough cases
▪ Despite high vaccine efficacy, vaccine breakthrough cases expected
– Some will be caused by variants, even if vaccine has similar effectiveness against variants
▪ Vaccine breakthrough case: person with SARS-CoV-2 RNA or antigen detected
in respiratory specimen collected ≥14 days after completing primary series of
an FDA-authorized COVID-19 vaccine
▪ Cases identified from national case-based surveillance, Vaccine Adverse
Events Reporting System (VAERS), health departments, healthcare providers
– Working with state health departments on case investigation
– Respiratory specimens used for whole genome sequencing to identify variants
▪ Data from investigations will be posted or published when availableBoosters and second-generation vaccines against SARS-
CoV-2 variants
▪ Moderna and Pfizer launching booster studies of current vaccines in U.S. and
developing second-generation vaccines against B.1.351
– Moderna: Variant-specific vaccine (mRNA-1273.351) and multivalent vaccine
with original authorized vaccine and variant vaccine (mRNA-1273.21)
▪ Yet to be defined:
– Evidence indicating need for a modified vaccine
– Process for evaluating, deciding and recommending whether a modified
vaccine is needed
▪ World Health Organization (WHO) has likely role in global coordination —
developing framework for risk assessment
https://investors.modernatx.com/news-releases/news-release-details/moderna-covid-19-vaccine-retains-neutralizing-activity-against
https://investors.modernatx.com/news-releases/news-release-details/moderna-announces-it-has-shipped-variant-specific-vaccine
https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-initiate-study-part-broad-developmentFDA: Data needed to support EUA amendment for
a vaccine addressing emerging SARS-CoV-2 variants
1. Good manufacturing practices and controls
2. Nonclinical data, e.g., laboratory studies, animal models
3. Clinical data from immunogenicity studies — noninferiority with licensed
vaccine
– Primary series or booster dose
– Could be single age group with extrapolation to other age groups
– Safety data from during the immunogenicity evaluation period
4. Laboratory assays and immunogenicity endpoints
– Correlates of protection not yet established
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/emergency-use-authorization-vaccines-prevent-covid-19Variants: Implications for vaccine policy
▪ Continue to monitor evidence:
– Emergence and spread of SARS-CoV-2 variants
– Vaccine effectiveness
– Breakthrough infections in vaccinated or previously infected persons
– Ability of postvaccination serum to neutralize emerging variant viruses
▪ Work Group and ACIP will review evidence submitted for any next
generation vaccinesFor more information, contact CDC 1-800-CDC-INFO (232-4636) TTY: 1-888-232-6348 www.cdc.gov Thank you The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.
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